Bicyclic benzamides of 3- or 4-substituted 4-(aminomethyl)-piperidine derivatives

ABSTRACT

The present invention of compounds of formula (I)                    
     a stereochemically isomeric form thereof, an N-oxide form thereof or a pharmaceutically acceptable acid addition salt thereof, R 1  and R 2  taken together form a bivalent radical of formula wherein in said bivalent radicals one or two hydrogen atoms may be substituted with C 1-6 alkyl; R 3  is hydrogen or halo; R 4  is hydrogen or C 1-6 alkyl; R 5  is hydrogen or C 1-6 alkyl; L is C 3-6 cycloalkyl, C 5-6 cycloalkanone, C 2-6 alkenyl, or L is a radical of formula —Alk—R 6 —, Alk—X—R 7 , —Alk—Y—C(═O)—R 9 , or —Alk—Y—C(═O)— NR 11 R 12  wherein each Alk is C 1-12 alkanediyl; and R 6  is hydrogen, cyano, C 1-6 alkylsulfonylamino, C 3-6 cycloalkyl, C 5-6 cycloalkanone, or a heterocyclic ringsystem; R 7  is hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 3-6 cycloalkyl, or a heterocyclic ringsystem; X is O, SO 2  or NR 8 ; said R 8  being hydrogen or C 1-6 alkyl; R 9  is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyloxy or hydroxy; Y is NR 10  or a direct bond; said R 10  being hydrogen, or C 1-6 alkyl; R 11  and R 12  each independently are hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or R 11  and R 12  combined with the nitrogen atom may form an optionally substituted pyrrolidinyl, piperidinyl, piperazinyl or 4-morpholinyl ring. Processes for preparing said products, formulations comprising said products and their use as a medicine are disclosed, in particular for treating conditions which are related to impairment of gastric emptying.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 09/349,912 filed onJul. 8, 1999 which is a continuation of U.S. Ser. No. 09/113,635 filedon Jul. 10, 1998, which claims priority from EPO application EP98.200.624.9 filed on Feb. 27, 1998 and EPO application EP97.202.180.2filed on Jul. 11, 1997.

The present invention is concerned with novel compounds of formula (I)having superior gastrokinetic properties. The invention further relatesto methods for preparing such novel compounds, pharmaceuticalcompositions comprising said novel compounds as well as the use as amedicine of said compounds.

Journal of Medicinal Chemistry, 1993, 36, pp 4121-4123 discloses4-amino-N-[(1-butyl-4-piperidinyl)methyl]-5-chloro-2-methoxy-benzamideas a potent and selective 5HT₄-receptor antagonist.

WO 93/05038, published on Mar. 18, 1993 (SmithKline Beecham PLC)discloses a number of substituted 4-piperidinylmethyl8-amino-7-chloro-1,4-benzodioxan-5-carboxamides having 5HT₄-receptorantagonistic activity.

WO 94/10174, published on May 11, 1994 (SmithKline Beecham PLC)discloses a number of substituted 4-pyridinylmethyloxazino[3,2-a]indole-carboxamide derivatives having 5HT₄-receptorantagonistic activity.

The above prior art documents all disclose substituted4-piperidinylmethyl carboxamides and the analogues thereof having5HT₄-receptor antagonistic activity. Compounds showing 5HT₄ antagonismare taught to have potential interest in the treatment of, for example,irritable bowel syndrome, in particular the diarrhoea aspects ofirritable bowel syndrome, i.e. these compounds block the ability of 5HT(which stands for 5-hydroxy-tryptamine, i.e. serotonin) to stimulate gutmotility (see WO-93/05038, page 8, lines 12 to 17). The presentgastroprokinetic compounds differ in structure mainly by the presence ofa hydroxy- or an alkyloxy group on the central piperidine ring.

WO 93/16072, published on Aug. 19, 1993 discloses5-amino-N-[(1-butyl-4-piperidinyl)methyl]-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamidehaving 5 HT₄ receptor antagonistic activity.

Bioorganic & Medicinal Chem. Lett., 1996, 6, pp. 263-266, andWO-96/33186 (Pharmacia S.P.A.), published on Oct. 24, 1996, disclose4-amino-N-(1-butyl-4-piperidinyl)methyl-5-chloro-2,3-dihydro-7-benzoturancarboxamidehaving 5 HT₄ receptor agonistic activity.

The compounds of the present invention differ from the previous priorart documents due to the presence of a hydroxy or a C₁₋₆alkyloxy groupon the 3 position of the central piperidine ring.

EP-0,299,566, published on Jan. 19, 1989, disclosesN-(3-hydroxy-4-piperidinyl)benzamides having gastrointestinal motilitystimulating activity.

EP-0,309,043, published on Mar. 29, 1989, discloses substitutedN-(1-alkyl-3-hydroxy-4-piperidinyl)benzamides having gastrointestinalmotility stimulating activity.

EP-0,389,037, published on Sep. 26, 1990, disclosesN-(3-hydroxy-4-piperidinyl)(dihydrobenzofuran, dihydro-2H-benzopyran ordihydrobenzodioxin)-carboxamide derivatives having gastrointestinalmotility stimulating activity.

The latter three prior art documents all disclose carboxamidederivatives wherein the amide function is bonded directly with thepiperidine ring, while the compounds of the present invention all havean amide function wherein a methylene group is present between thecarbamoyl nitrogen and the piperidine ring.

EP-0,774,460, published on May 21, 1997, and WO-97/11054, published onMar. 27, 1997 disclose a number of benzoic acid compounds as 5-HT₄agonists useful for treating gastric motility disorders.

The compounds of the present invention differ from the latter two priorart documents due to the presence of a hydroxy or a C₁₋₆alkyloxy groupon the 3- or 4-position of the central piperidine ring. Furthermore,those compounds of the present invention wherein R² is other thanhydrogen are also structurally different over said prior art documents.

The problem this invention sets out to solve is to provide compoundshaving gastrointestinal motility stimulating properties, particularlyhaving superior gastric emptying activity. Preferably said compoundsshould be orally active.

The solution to this problem is provided by the novel compounds offormula (I) that differ structurally from the prior art, inter alia, bythe presence of a hydroxy or a C₁₋₆alkyloxygroup on the 3- or 4-positionof the central piperidine ring, or by the presence of a methylene groupbetween the carbamoyl group and the piperidine ring.

The present invention concerns a compound of formula (I)

a stereochemically isomeric form thereof, an N-oxide form thereof or apharmaceutically acceptable acid or base addition salt thereof,

wherein

R¹ and R² taken together form a bivalent radical of formula

—O—CH₂—O— (a-1),

—O—CH₂—CH₂— (a-2),

—O—CH₂—CH₂—O— (a-3),

—O—CH₂—CH₂—CH₂— (a-4),

—O—CH₂—CH₂—CH₂—O— (a-5),

—O—CH₂—CH₂—CH₂—CH₂— (a-6),

wherein in said bivalent radicals one or two hydrogen atoms may besubstituted with C₁₋₆alkyl,

R³ is hydrogen or halo;

R⁴ is hydrogen or C₁₋₆alkyl;

R⁵ is hydrogen or C₁₋₆alkyl;

L is C₃₋₆cycloalkyl, C₅₋₆cycloalkanone, or C₂₋₆alkenyl, or L is aradical of formula

—Alk—R⁶ (b-1),

—Alk—X—R⁷ (b-2),

—Alk—Y—C(═O)—R⁹ (b-3), or

—Alk—Y—C(═O)—NR¹¹R¹² (b-4),

wherein each Alk is C₁₋₁₂alkanediyl; and

R⁶ is hydrogen, hydroxy, cyano, C₁₋₆alkylsulfonylamino, C₃₋₆cycloalkyl,C₅₋₆cycloalkanone, or Het¹;

R⁷ is hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₃₋₆cycloalkyl, or Het²;

X is O, S, SO₂ or NR⁸; said R⁸ being hydrogen or C₁₋₆alkyl;

R⁹ is hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkyloxy or hydroxy;

Y is NR¹⁰ or a direct bond, said R¹⁰ being hydrogen or C₁₋₆alkyl;

R¹¹ and R¹² each independently are hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl,or R¹¹ and R¹²combined with the nitrogen atom bearing R¹¹ and R¹² mayform a pyrrolidinyl or piperidinyl ring both being optionallysubstituted with C₁₋₆alkyl, amino or mono or di(C₁₋₆alkyl)amino, or saidR¹¹ and R¹² combined with the nitrogen bearing R¹¹ and R¹² may form apiperazinyl or 4-morpholinyl radical both being optionally substitutedwith C₁₋₆alkyl; and

Het¹ and Het² each independently are selected from furan: furansubstituted with C₁₋₆alkyl or halo; tetrahydrofuran; a tetrahydrofuransubstituted with C₁₋₆alkyl; a dioxolane; a dioxolane substituted withC₁₋₆alkyl, a dioxane; a dioxane substituted with C₁₋₆alkyl;tetrahydropyran; a tetrahydropyran substituted with C₁₋₆alkyl;pyrrolidinyl; pyrrolidinyl substituted with one or two substituents eachindependently selected from halo, hydroxy, cyano, or C₁₋₆alkyl;pyridinyl; pyridinyl substituted with one or two substituents eachindependently selected from halo, hydroxy, cyano, C₁₋₆alkyl;pyrimidinyl; pyrimidinyl substituted with one or two substituents eachindependently selected from halo, hydroxy, cyano, C₁₋₆alkyl,C₁₋₆alkyloxy, amino and mono and di(C₁₋₆alkyl)amino; pyridazinyl;pyridazinyl substituted with one or two substituents each independentlyselected from hydroxy, C₁₋₆alkyloxy, C₁₋₆alkyl or halo; pyrazinyl;pyrazinyl substituted with one ore two substituents each independentlyselected from halo, hydroxy, cyano, C₁₋₆alkyl, C₁₋₆alkyloxy, amino,mono- and di(C₁₋₆alkyl)amino and C₁₋₆alkyloxycarbonyl;

Het¹ can also be a radical of formula

Het¹ and Het² each independently can also be selected from the radicalsof formula

R¹³ and R¹⁴ each independently are hydrogen or C₁₋₄alkyl.

As used in the foregoing definitions halo is generic to fluoro, chloro,bromo and iodo; C₁₋₄alkyl defines straight and branched chain saturatedhydrocarbon radicals having from 1 to 4 carbon atoms such as, forexample, methyl, ethyl, propyl, butyl, 1-methyl-ethyl, 2-methylpropyland the like; C₁₋₆alkyl is meant to include C₁₋₄alkyl and the higherhomologues thereof having 5 or 6 carbon atoms, such as, for example,2-methyl-butyl, pentyl, hexyl and the like; C₃₋₆cycloalkyl is generic tocyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C₂₋₆alkenyl definesstraight and branched chain unsaturated hydrocarbon radicals having from2 to 6 carbon atoms, such as ethenyl, propenyl, butenyl, pentenyl orhexenyl; C₁₋₁₂alkanediyl defines bivalent straight or branched chainhydrocarbon radicals containing from 1 to 12 carbon atoms such as, forexample, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl,1,5-pentanediyl, 1,6-hexanediyl, 1,7-heptanediyl, 1,8-octanediyl,1,9-nonanediyl, 1,10-decanediyl, 1,11-undecanediyl, 1,12-dodecanediyland the branched isomers thereof. C₁₋₆alkanediyl is defined in ananalogous way as C₁₋₁₂alkanediyl.

The —OR⁴ radical is preferably situated at the 3- or 4-position of thepiperidine moiety.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible isomeric forms which the compounds of formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. More inparticular, stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or trans-configuration. Compounds encompassing doublebonds can have an E or Z-stereochemistry at said double bond.Stereochemically isomeric forms of the compounds of formula (I) areobviously intended to be embraced within the scope of this invention.

The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove are meant to comprise the therapeutically activenon-toxic acid and base addition salt forms which the compounds offormula (I) are able to form. The pharmaceutically acceptable acidaddition salts can conveniently be obtained by treating the base formwith such appropriate acid. Appropriate acids comprise, for example,inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid, sulfuric, nitric, phosphoric and the like acids: ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.butane-dioic acid), maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds of formula (I) containing an acidic proton may also beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts withamino acids such as, for example, arginine, lysine and the like.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) as well as the salts thereof, areable to form. Such solvates are for example hydrates, alcoholates andthe like.

Some of the compounds of formula (I) may also exist in their tautomericform. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.For instance, when an aromatic heterocyclic ring is substituted withhydroxy the keto-form may be the mainly populated tautomer.

The N-oxide forms of the compounds of formula (I), which may be preparedin art-known manners, are meant to comprise those compounds of formula(I) wherein one or several nitrogen atoms are oxidized to the N-oxide.Particularly those N-oxides are envisaged wherein thepiperidine-nitrogen is N-oxidized.

A group of interesting compounds consists of those compounds of formula(I) wherein one or more of the following restrictions apply:

a) R¹ and R² taken together form a radical of formula (a-1), (a-2),(a-3), (a-4), (a-5) or (a-6), wherein optionally one or two hydrogenatoms are substituted with C₁₋₄alkyl;

b) R³ is fluoro, chloro or bromo; in particular chloro;

c) R⁴ is hydrogen or methyl, and the —OR⁴ radical is situated at the 3-or 4-position of the piperidine ring; or

d) R⁵ is hydrogen.

More interesting compounds are those compounds of formula (I) wherein R¹and R² taken together form a radical of formula (a-2), or (a-4), whereinoptionally one or two hydrogen atoms are substituted with methyl.

Further more interesting compounds are those interesting compounds offormula (I) wherein R⁴ is hydrogen or methyl.

Particular compounds are those more interesting compounds wherein the—OR⁴ radical is situated at the 3-position of the central piperidinemoiety having the trans configuration, i.e. the —OR⁴ radical is in thetrans position in relation to the methylene on the central piperidinemoiety.

Other particular compounds are those more interesting compounds whereinthe —OR⁴ radical is situated at the 4-position of the central piperidinemoiety.

Very particular compounds are those compounds wherein L is:

C₃₋₆cycloalkyl or C₂₋₆alkenyl; or

a radical of formula (b-1), wherein each Alk is C₁₋₆alkanediyl, and R⁶is hydrogen, hydroxy, cyano, amino, C₁₋₆alkylsulfonylamino,C₃₋₆cycloalkyl or Het¹, wherein Het¹ is tetrahydrofuran; dioxolane;dioxolane substituted with C₁₋₆alkyl; tetrahydropyran; pyridazinylsubstituted with one or more substituents selected from hydroxy, haloand C₁₋₆alkyl; or a radical of formula (c-1), (c-3) or (c-4) wherein R¹³is C₁₋₄alkyl; or

a radical of formula (b-2), wherein Alk is C₁₋₆alkanediyl, X is O, andR⁷ is C₁₋₆alkyl or hydroxyC₁₋₆alkyl; or

a radical of formula (b-2), wherein Alk is C₁₋₆alkanediyl, R⁷ is Het²wherein Het² is pyrazinyl substituted with C₁₋₆alkyl, and X is NR⁸wherein R⁸ is hydrogen or C₁₋₆alkyl; or

a radical of formula (b-3) wherein Y is a direct bond, and R⁹ isC₁₋₆alkyl, hydroxy or C₁₋₆alkyloxy; or

a radical of formula (b-4) wherein Y is a direct bond, and R¹¹ and R¹²are C₁₋₆alkyl, or

R¹¹ and R¹² combined with the nitrogen atom bearing R¹¹ and R¹² formpyrrolidinyl.

Preferred compounds are those compounds wherein L is butyl; propylsubstituted with methoxy, methylcarbonyl or 2-methyl-1,3-dioxolane;ethyl substituted with 4-methyl-2-pyridazinone or tetrahydropyranyl; ormethyl substituted with tetrahydrofuranyl or tetrahydropyranyl.

Most preferred are:

trans-4-amino-N-[(1-butyl-3-hydroxy-4-piperidinyl)methyl]-5-chloro-2,3-dihydro-7-benzofurancarboxamide,

trans-4-amino-5-chloro-2,3-dihydro-N-[[3-hydroxy-1-(3-methoxypropyl)-4-piperidinyl]methyl]-7-benzofurancarboxamide,

trans-4-amino-5-chloro-2,3-dihydro-N-[3-hydroxy-1-[(tetrahydro-2-furanyl)methyl]-4-piperidinyl]-7-benzofurancarboxamide,

trans-4-amino-5-chloro-2,3-dihydro-N-[[3-hydroxy-1-(4-oxopentyl)-4-piperidinyl]methyl]-7-benzofurancarboxamide,

trans-4-amino-5-chloro-2,3-dihydro-N-[3-hydroxy-1-[(tetrahydro-2-pyranyl)methyl]-4-piperidinyl]-7-benzofurancarboxamide,

trans-4-amino-5-chloro-2,3-dihydro-N-[[3-methoxy-1-(3-methoxypropyl)-4-piperidinyl]methyl]-7-benzofurancarboxamide,

trans-4-amino-5-chloro-2,3-dihydro-N-[[3-methoxy-1-[(tetrahydro-2-furanyl)methyl]-4-piperidinyl]methyl]-7-benzofurancarboxamide,

trans-4-amino-5-chloro-2,3-dihydro-N-[[3-hydroxy-1-(3-methoxypropyl)-4-piperidinyl]methyl]-2,2-dimethyl-7-benzofurancarboxamide,

trans-4-amino-5-chloro-2,3-dihydro-N-[[3-methoxy-1-(4-oxopentyl)-4-piperidinyl]methyl]-7-benzofurancarboxamide,

trans-5-amino-N-[(1-butyl-3-hydroxy-4-piperidinyl)methyl]-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide,and the stereoisomeric forms, the pharmaceutically acceptable acid orbase addition salts, or the N-oxides thereof; and

trans-(−)-4-amino-5-chloro-2,3-dihydro-N-[[3-hydroxy-1-(3-methoxypropyl)-4-piperidinyl]methyl]-2,2-dimethyl-7-benzofurancarboxamide,a pharmaceutically acceptable acid addition salt or an N-oxide formthereof.

The compounds of the present invention can generally be prepared byN-alkylating an intermediate of formula (III) with an intermediate offormula (II), wherein W is an appropriate leaving group such as, forexample, halo, e.g. fluoro, chloro, bromo, iodo, or in some instances Wmay also be a sulfonyloxy group, e.g. methanesulfonyloxy,benzenesulfonyloxy, trifluoromethanesulfonyloxy and the like reactiveleaving groups. The reaction can be performed in a reaction-inertsolvent such as, for example, acetonitrile, and optionally in thepresence of a suitable base such as, for example, sodium carbonate,potassium carbonate or triethylamine. Stirring may enhance the rate ofthe reaction. The reaction may conveniently be carried out at atemperature ranging between room temperature and the reflux temperatureof the reaction mixture.

Alternatively, compounds of formula (I) can also be prepared byreductively N-alkylating an intermediate of formula (III) with anintermediate of formula L′═O (IV), wherein L′═O represents a derivativeof formula L—H wherein two geminal hydrogen atoms are replaced byoxygen, following art-known reductive N-alkylation procedures.

Said reductive N-alkylation can be performed in a reaction-inert solventsuch as, for example, dichloromethane, ethanol, toluene or a mixturethereof, and in the presence of a reducing agent such as, for example, aborohydride, e.g. sodium borohydride, sodium cyanoborohydride ortriacetoxy borohydride. It may also be convenient to use hydrogen as areducing agent in combination with a suitable catalyst such as, forexample, palladium-on-charcoal or platinum-on-charcoal. In case hydrogenis used as reducing agent, it may be advantageous to add a dehydratingagent to the reaction mixture such as, for example, aluminiumtert-butoxide. In order to prevent the undesired further hydrogenationof certain functional groups in the reactants and the reaction products,it may also be advantageous to add an appropriate catalyst-poison to thereaction mixture, e.g., thiophene or quinoline-sulphur. To enhance therate of the reaction, the temperature may be elevated in a range betweenroom temperature and the reflux temperature of the reaction mixture andoptionally the pressure of the hydrogen gas may be raised.

The compounds of formula (I) may be prepared by reacting an intermediateof formula (V) with an carboxylic acid derivative of formula (VI) or areactive functional derivative thereof, such as for example carbonylimidazole derivatives. Said amide-bond formation may be performed bystirring the reactants in an appropriate solvent, optionally in thepresence of a base, such as sodium imidazolide.

Further, compounds of formula (I) can be prepared by carbonylation of anintermediate of formula (VII), wherein X is bromo or iodo, in thepresence of an intermediate of formula (V).

Said carbonylation reaction can be carried out in a reaction-inertsolvent such as, e.g. acetonitrile or tetrahydrofuran, in the presenceof a suitable catalyst and a suitable base such as a tertiary amine e.g.triethylamine, and at a temperature ranging between room temperature andthe reflux temperature of the reaction mixture. Suitable catalysts are,for instance, palladium(triphenylphosphine) complexes. Carbon monoxideis administered at atmospheric pressure or at an increased pressure.Analogous carbonylation reactions are described in Chapter 8 of“Palladium reagents in organic syntheses”, Academic Press Ltd., BenchtopEdition 1990, by Richard F. Heck; and the references cited therein.

Said amide formation reaction is known from the above mentionedreference with metal catalysts which are soluble such as palladium(triphenylphosphine) complexes. Unexpectedly, we deem to have found thatthese reactions can also be performed on metal catalysts which areinsoluble or immobilized on a solid carrier. Suitable catalysts are forexample palladium-on-carbon. Raney nickel or Cu₂O. These insolublecatalysts or catalysts on a solid phase are much less expensive than themetal complexes and are often much easier to handle when synthesis isdone on an industrial scale.

In other words, we have found a novel and inventive way to prepareamides in the following way:

In the above formulas Rd represent any substituent possible on a phenyl,n is an integer from 1 to 5, and R′R″NH can be any primary or secundaryamine. The term halide suitably refers to chloro, bromo, iodo. Preferredhalides are bromo and iodo.

The preferred catalyst is palladium-on-carbon.

The pressure of CO, i.e. carbon monoxide, may vary according to thesubstrates and reactants and a person skilled in the art will certainlybe able to find a suitable range after little straightforwardexperimentation. The preferred pressure of CO, i.e. carbon monoxide, is50 kg/cm² (about 4.9×10⁶ Pa). It may suitably range between about 1kg/cm² (about 1×10⁵ Pa) and about 100 kg/cm² (about 10×10⁶ Pa).

The reaction temperature may range from room temperature to the refluxtemperature of the reaction mixture.

This reaction is preferably performed in a solvent, which can be in theamine R′R″NH itself, or in acetonitrile or in tetrahydrofuran.

Preferably said R′R″NH amine is a primary amine.

Suitably a base is also present. An interesting suitable base is forinstance triethylamine.

The starting materials and some of the intermediates are known compoundsand are commercially available or may be prepared according toconventional reaction procedures generally known in the art. Forexample, a number of intermediates of formula (VI) may be preparedaccording to art-known methodologies described in EP-0,389,037.

However, some intermediates of formula (VI) are novel and, hence, theinvention also provides novel intermediates of formula (VI) wherein R¹is methoxy, R² is methyl or methoxy and R³ is chloro. Said novelintermediates of formula (VI) are prepared as described in Example A.3.

An intermediate of formula (III) may be prepared by reacting anintermediate of formula (VIII), wherein PG represents an appropriateprotective group, such as for example a tert-butoxycarbonyl or a benzylgroup or a photoremovable group, with an acid of formula (VI), or anappropriate reactive functional derivative thereof, such as for examplecarbonyl imidazole derivatives, and subsequent deprotection of the thusformed intermediate, i.e. removal of PG by art-known methods.

An intermediate of formula (V) may be prepared by reacting anintermediate of formula (X), with an intermediate of formula (II). Saidintermediate of formula (X) may be prepared by deprotection of anintermediate of formula (VIII).

In some cases, it may be appropriate to protect the amine functionalitybearing the R⁵ radical in the above described reaction sequence.Protecting groups for amine functionalities are art-known. Theseprotecting groups may then be removed at the appropriate time during thefurther synthesis.

Intermediates of formula (VIII-a), being intermediates of formula (VIII)wherein PG¹ is a protecting group which cannot be removed byhydrogenation such as e.g. a tert-butoxycarbonyl, can be preparedaccording to scheme 1.

In scheme 1, an intermediate of formula (XI-a) is converted to anintermediate of formula (XII), wherein W¹ is a leaving group such ashalo or sulfonyloxy. Subsequently, intermediate (XII) is treated with anintermediate of formula (XIII), wherein PG² is a protecting group whichcan be removed by hydrogenation such as, e.g. benzyl. Removal of theprotecting group PG² from intermediate (XIV) yields intermediates offormula (VIII-a).

Intermediates of formula (VII-a-1), defined as intermediates of formula(VIII-a) wherein R⁴ is methyl, can be prepared as described in scheme 2.

In scheme 2, an intermediate of formula (XI-a), wherein R^(4a) ishydrogen, is converted to an intermediate of formula (XII-1), wherein W²is a suitable leaving group such as e.g. a tosylate group. Subsequently,the secundary hydroxy of intermediate (XII-1), i.e. the —OR^(4a) moiety,is converted to a methoxy using suitable methylation conditions such ase.g. treatment with sodium hydride in tetrahydrofuran and addition ofmethyliodide. Conversion of intermediate (XX) to intermediate (VII-a-1)can be done using art-known reaction procedures.

In an aspect of the present invention, novel compounds of formula (IX)are provided wherein R¹⁵ and R¹⁶ are each independently selected fromhydrogen or a protective group PG, and R⁴ and R⁵ are as defined above.Suitable protecting groups PG are, e.g. C₁₋₄alkylcarbonyl,C₁₋₄alkyloxycarbonyl, trihalomethylcarbonyl, diphenylmethyl,triphenylmethyl or arylmethyl, wherein aryl is phenyl optionallysubstituted with up to two substituents selected from C₁₋₄alkyloxy orhalo. Said novel compounds of formula (IX) comprise the intermediates offormula (VIII), (X) and (XIV).

Intermediates of formula (XI-a), wherein PG¹ is a protecting group whichcannot be removed by hydrogenation such as e.g. a tert-butoxycarbonyl,can be converted to intermediates of formula (XI-b), wherein PG² is aprotecting group which can be removed by hydrogenation such as, e.g.benzyl, using an appropriate deprotection-protection reaction sequence.Conversely, intermediates of formula (XI-b) can also be converted tointermediates of formula (XI-a).

An intermediate of formula (XI-b), wherein the —OR⁴ moiety is located onthe 3-position of the piperidine moiety, R⁴ is a hydrogen and PG² is abenzyl group, having the trans configuration, is known from J. Med.Chem., 16, pp. 156-159 (1973). Said article also describes anintermediate of formula (XIX), wherein the —OR⁴ moiety is located on the3-position of the piperidine moiety and R⁴ is a hydrogen, having thetrans configuration.

Intermediates of formula (XI-1-a) are defined as intermediates offormula (XI-a) wherein the —OR⁴ moiety is located on the 3-position ofthe piperidine moiety.

Those intermediates of formula (XI-1-a) wherein R⁴ is C₁₋₆alkyl andhaving the cis configuration can be prepared by hydrogenating anintermediate of formula (XVI) following art-known methods. Theintermediate (XVI), wherein PG¹ and PG² are as defined above, can beprepared by reacting a protected piperidone of formula (XV) with aphosphonium reagent of formula [(aryl)₃P—CH₂—O—PG²]⁺-halide⁻, inappropriate conditions for carrying out a Wittig-type reaction.Subsequent removal of PG² yields intermediates of formula (XI-1-a)having the cis configuration.

A novel way of preparing an intermediate of formula (XI-1-b) having thetrans-configuration was found. Said novel preparation starts from anintermediate of formula (XI-1-b) having the cis-configuration or from anintermediate of formula (XVII) having the cis-configuration. In saidintermediates of formula (XI-1-b) and (XVII) PG² is as defined above,R^(4a) is hydrogen, C₁₋₆alkyl or a protective group such as for example,benzyl, tert-butoxycarbonyl and the like.

Said inversion-reaction is carried out in an appropriate solvent, suchas, for example an ether, e.g. tetrahydrofuran in the presence ofCuO.Cr₂O₃ under a hydrogen atmosphere and in the presence of anappropriate base, such as, for example calciumoxide.

The preferred hydrogen pressure and reaction temperature is dependentupon the starting material. Starting from cis-(XI-1-b) the hydrogenpressure preferably ranges from 900 to 2000 kPa (measured at roomtemperature) and the reaction temperature ranges from room temperatureup to 200° C. preferably the reaction temperature is about 120° C.

When starting from cis-(XVII), the preferred hydrogen pressure range isfrom 1500 kPa to 2200 kPa, preferably between 1800 kPa to 2000 kPa. Thereaction temperature is between 100° C. and 200° C. preferably at about125° C. Apparently an equilibrium is reached, typically with adiastereomeric ratio of about 65:35 (trans:cis) as determined by gaschromatography. However via recrystallization it is possible to purifythe desired trans-isomer. A suitable solvent for recrystallization is anether, e.g. diisopropyl ether.

The pure intermediate of formula trans-(XI-1-b) having the transconfiguration can also be obtained by chromatographic techniques, suchas, for example gravitation chromatography or (H)PLC, starting from thecis/trans mixture of the intermediate (XI-1-b).

Still another novel way of preparing intermediates of formulatrans-(XI-1-b) is to react an intermediate of formula (XVII) with boraneor a borane derivative. Borane itself is commercially available as aborane-tetrahydrofuran complex. Borane derivatives, especially chiralborane derivatives are also commercially available. The reaction withborane is performed in a reaction inert solvent, preferable an ether,e.g. tetrahydrofuran. While adding the borane or the borane derivativethe reaction mixture is kept at temperatures below 0° C., interestinglyat a temperature of about −30° C. After adding the borane or the boranederivative to the reaction mixture the mixture is allowed to heat upwhile stirring is continued. The mixture is stirred for several hours.Subsequently, a hydroxide, e.g. sodium hydroxide is added as well as aperoxide, e.g. hydrogen peroxide and the reaction mixture is stirred atelevated temperatures for several hours. After this treatment thereaction product was isolated in art-known manner.

Intermediates of formula (XVIII) can be prepared by reacting anintermediate of formula (XXI), wherein PG² is as defined above and W isa leaving group as defined above, with an intermediate of formula(XXII), and subsequent reduction of the so-obtained intermediate (XXIII)with sodium borohydride, yielding intermediates of formula (XVIII).

Said reaction procedure can also be used to prepare intermediates offormula (V). Consequently, an intermediate of formula (II) is reactedwith an intermediate of formula (XXII) and the so-obtained intermediateof formula (XXIV) is reduced to an intermediate of formula (XXV) usingsodium borohydride. Subsequently, the intermediates of formula (XXV) areconverted to intermediates of formula (XXVI) using the above-describedreaction procedure for the conversion of intermediates (XVIII) tointermediates of formula trans-(XI-b).

Intermediates of formula (XXVI) can be converted to intermediates offormula (V) having the trans configuration, using a reaction procedureas describe above in Scheme 1 or Scheme 2.

Intermediates of formula (VIII-a) are defined as intermediates offormula (VIII) wherein the —OR⁴ moiety is located on the 4-position ofthe piperidine moiety and R⁴ is hydrogen.

Said intermediates of formula (VIII-a) can be prepared by reacting anintermediate of formula (XXVII) with nitromethane under suitablereaction conditions, such as, e.g. sodium methoxide in methanol, andsubsequently converting the nitro group into an amine group, therebyyielding the intermediates of formula (VIII-a).

Intermediates of formula (V-a), defined as intermediates of formula (V)wherein R⁵ is hydrogen, can be prepared as following:

An intermediate of formula (II) is reacted with an intermediate offormula (XXIX), wherein PG³ is a suitable protecting group such asρ-toluenesulfonyl, and the so-obtained intermediate of formula (XXX) isreduced to an intermediate of formula (XXXI) using sodium borohydride.Subsequently, the intermediates of formula (XXXI) are converted tointermediates of formula (XXXII) using the above-described reactionprocedure for the conversion of intermediates (XVIII) to intermediatesof formula trans-(XI-b). Subsequently, removing the protecting group PG³from intermediates (XXXII) yields the intermediates of formula (V-a).

The compounds of formula (I), the N-oxide forms, the pharmaceuticallyacceptable salts and stereoisomeric forms thereof possess favourableintestinal motility stimulating properties. In particular the presentcompounds show significant gastric emptying activity as is evidenced inpharmacological example C-1, the “Gastric emptying of an acaloric liquidmeal delayed by administration of lidamidine in conscious dogs”-test.

The compounds of formula (I) also are shown to have a beneficial effectsuch as increase of basal pressure of the LES, i.e. Lower EsophagealSphincter.

Most of the intermediates of formula (III) have shown to have analogousactivity as the final compounds of formula (I).

In view of the capability of the compounds of the present invention toenhance the gastrointestinal motility, and in particular to activategastric emptying, the subject compounds are useful to treat conditionsrelated to a hampered or impaired gastric emptying and more generally totreat conditions related to a hampered or impaired gastrointestinaltransit.

In view of the utility of the compounds of formula (I), it follows thatthe present invention also provides a method of treating warm-bloodedanimals, including humans, (generally called herein patients) sufferingfrom conditions related to a hampered or impaired gastric emptying ormore generally suffering from conditions related to a hampered orimpaired gastrointestinal transit. Consequently a method of treatment isprovided for relieving patients suffering from conditions, such as, forexample, gastro-oesophageal reflux, dyspepsia, gastroparesis,constipation, post-operative ileus, and intestinal pseudo-obstruction.Gastroparesis can be brought about by an abnormality in the stomach oras a complication of diseases such as diabetes, progressive systemicsclerosis, anorexia nervosa and myotonic dystrophy. Constipation canresult from conditions such as lack of intestinal muscle tone orintestinal spasticity. Post-operative ileus is an obstruction or akinetic impairment in the intestine due to a disruption in muscle tonefollowing surgery. Intestinal pseudo-obstruction is a conditioncharacterized by constipation, colicky pain, and vomiting, but withoutevidence of physical obstruction. The compounds of the present inventioncan thus be used either to take away the actual cause of the conditionor to relief the patients from symptoms of the conditions. Dyspepsia isan impairment of the function of digestion, that can arise as a symptomof a primary gastrointestinal dysfunction, especially a gastrointestinaldysfunction related to an increased muscle tone or as a complication dueto other disorders such as appendicitis, galbladder disturbances, ormalnutrition.

The symptoms of dyspepsia may also arise due to the intake of chemicalsubstances, e.g. Selective Seretonine Re-uptake Inhibitors (SSRI's),such as fluoxetine, paroxetine fluvoxamine, and sertraline.

Additionally some of the compounds also are stimulators of kineticactivity on the colon.

Hence, the use of a compound of formula (I) as a medicine is provided,and in particular the use of a compound of formula (I) for themanufacture of a medicine for treating conditions involving a decreasedgastrointestinal motility, in particular decreased gastric emptying.Both prophylactic and therapeutic treatment are envisaged.

To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound, in base or acid additionsalt form, as the active ingredient is combined in intimate admixturewith a pharmaceutically acceptable carrier, which carrier may take awide variety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally or by parenteral injection. For example, in preparing thecompositions in oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, oils, alcoholsand the like in the case of oral liquid preparations such assuspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notcause a significant deleterious effect to the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. Acid addition salts of (I) due to theirincreased water solubility over the corresponding base form, areobviously more suitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

For oral administration, the pharmaceutical compositions may take theform of solid dose forms, for example, tablets (both swallowable-onlyand chewable forms), capsules or gelcaps, prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium phosphate); lubricants e.g. magnesium stearate, talc or silica);disintegrants (e.g. potato starch or sodium starch glycollate); orwetting agents (e.g. sodium lauryl sulphate). The tablets may be coatedby methods well known in the art.

Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means,optionally with pharmaceutically acceptable additives such as suspendingagents (e.g. sorbitol syrup, methylcellulose, hydroxypropylmethylcellulose or hydrogenated edible fats); emulsifying agents (e.g.lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily estersor ethyl alcohol); and preservatives (e.g. methyl or propylp-hydroxybenzoates or sorbic acid).

Pharmaceutically acceptable sweeteners comprise preferably at least oneintense sweetener such as saccharin, sodium or calcium saccharin,aspartame, acesulfame potassium, sodium cyclamate, alitame, adihydrochalcone sweetener, monellin, stevioside or sucralose(4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose), preferablysaccharin, sodium or calcium saccharin, and optionally a bulk sweetenersuch as sorbitol, mannitol, fructose, sucrose, maltose, isomalt,glucose, hydrogenated glucose syrup, xylitol, caramel or honey.

Intense sweeteners are conveniently employed in low concentrations. Forexample, in the case of sodium saccharin, the concentration may rangefrom 0.04% to 0.1% (w/v) based on the total volume of the finalformulation, and preferably is about 0.06% in the low-dosageformulations and about 0.08% in the high-dosage ones. The bulk sweetenercan effectively be used in larger quantities ranging from about 10% toabout 35%, preferably from about 10% to 15% (w/v).

The pharmaceutically acceptable flavours which can mask the bittertasting ingredients in the low-dosage formulations are preferably fruitflavours such as cherry, raspberry, black currant or strawberry flavour.A combination of two flavours may yield very good results. In thehigh-dosage formulations stronger flavours may be required such asCaramel Chocolate flavour, Mint Cool flavour. Fantasy flavour and thelike pharmaceutically acceptable strong flavours. Each flavour may bepresent in the final composition in a concentration ranging from 0.05%to 1% (w/v). Combinations of said strong flavours are advantageouslyused. Preferably a flavour is used that does not undergo any change orloss of taste and colour under the acidic conditions of the formulation.

The formulations of the present invention may optionally include ananti-flatulent, such as simethicone, alpha-D-galactosidase and the like.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds may beformulated with suitable polymeric or hydrophobic materials (for exampleas an emulsion in an acceptable oil) or ion exchange resins, or assparingly soluble derivatives, for example as a sparingly soluble salt.

The compounds of the invention may be formulated for parenteraladministration by injection, conveniently intravenous, intramuscular orsubcutaneous injection, for example by bolus injection or continuousintravenous infusion. Formulations for injection may be presented inunit dosage form e.g. in ampoules or in multidose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as isotonizing, suspending, stabilising and/ordispersing agents. Alternatively, the active ingredient may be in powderform for constitution with a suitable vehicle, e.g. sterile pyrogen-freewater before use.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration the compounds of the invention may beused, for example, as a liquid spray, as a powder or in the form ofdrops.

In general it is contemplated that a therapeutically effective amountwould be from about 0.001 mg/kg to about 2 mg/kg body weight, preferablyfrom about 0.02 mg/kg to about 0.5 mg/kg body weight. A method oftreatment may also include administering the active ingredient on aregimen of between two or four intakes per day.

Experimental Part

In the procedures described hereinafter the following abbreviations wereused: “ACN” stands for acetonitrile: “THF”, which stands fortetrahydrofuran: “DCM” stands for dichloromethane; “DIPE” stands fordiisopropylether “EtOAc” stands for ethyl acetate; “NH₄OAc” stands forammonium acetate: “HOAc” stands for acetic acid; “MIK” stands for methylisobutyl ketone.

For some chemicals the chemical formula was used, e.g. NaOH for sodiumhydroxide, K₂CO₃ for potassium carbonate. H, for hydrogen gas, MgSO₄ formagnesium sulfate, CuO.Cr₂O₃ for copper chromite. N₂ for nitrogen gas,CH₂Cl₂ for dichloromethane, CH₃OH for methanol, NH₃ for ammonia. HCl forhydrochloric acid, NaH for sodium hydride, CaCO₃ for calcium carbonate,CO for carbon monoxide, and KOH for potassium hydroxide.

Of some compounds of formula (I) the absolute stereochemicalconfiguration was not experimentally determined. In those cases thestereochemically isomeric form which was first isolated is designated as“A” and the second as “B”, without further reference to the actualstereochemical configuration.

A. Preparation of the Intermediates

EXAMPLE A.1

a) A solution of 4-pyridinemethanol (1.84 mol) in ACN (1000 ml) wasadded to a solution of benzylchloride (2.2 mol) in ACN (1000 ml) and thereaction mixture was refluxed for 3 hours, cooled to room temperatureand evaporated. The residue was suspended in diethylether, filtered anddried, yielding 1-(phenylmethyl)-4-(hydroxy-methyl)-pyridinyl chloride(411 g, 97%).

b) 1-(Phenylmethyl)-4-(hydroxymethyl)-pyridinyl chloride(0.87 mol) wasdissolved in methanol (2200 ml) and cooled to −20° C. Sodium borohydride(1.75 mol) was added portionwise under a nitrogen atmosphere. Thereaction mixture was stirred for 30 minutes and water (200 ml) was addeddropwise. The reaction mixture was partially evaporated, water was addedand the reaction mixture was extracted with DCM. The organic layer wasseparated, dried, filtered and evaporated. The residue was purified oversilica gel (eluent: DCM), yielding 155 g1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinemethanol.

EXAMPLE A.2

a) A solution of 1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinemethanol(0.5 mol) in THF (1000 ml) was cooled to −30° C. and was added dropwiseunder a nitrogen atmosphere to a solution of borane in THF (1 M, 1000ml) while the reaction mixture was kept at a temperature between −20° C.and −30° C. After the addition, the reaction mixture was stirred for 4hours, allowed to warm up to room temperature and stirred at roomtemperature for 18 hours. The reaction mixture was cooled to −10° C. andwater (25 ml) was added dropwise. Then, simultaneously, NaOH (3M inwater, 70 ml) and the hydrogen peroxide (30% solution in water. 63.3 ml)was added dropwise while the reaction mixture was kept at a temperatureof −10° C. Again NaOH (50% in water, 140 ml) was added. The reactionmixture was stirred at reflux for 4 hours. The reaction mixture wascooled and filtered. The filtrate was evaporated. The resultingprecipitate was dissolved in water (500 ml) and saturated with K₂CO₃.The product was extracted with DCM. The resulting solution was driedover MgSO₄ and evaporated. The residue was crystallized from DIPE/CH₃CN.After several crystallizations(±)-trans-1-(phenyl-methyl)-3-hydroxy-4-piperidinemethanol was obtained(Yield: 50.1%)

b) A mixture of(±)-trans-1-(phenylmethyl)-3-hydroxy-4-piperidinemethanol (17.8 g, 0.085mol) (already described in J. Med. Chem., 16, pp. 156-159 (1973)) inmethanol (250 ml) was hydrogenated, at 50° C., with palladium onactivated carbon (10%, 2 g) as catalyst. After uptake of H₂ (1equivalent), the catalyst was filtered off and the filtrate wasevaporated, yielding 12 g of (±)-trans-3-hydroxy-4-piperidinemethanol(interm. 1-a) (used in next reaction step without further purification).The corresponding cis-isomer is known from J. Org. Chem., 34, pp.3674-3676 (1969).

c) A mixture of intermediate (1-a) (0.086 mol) in DCM (250 ml) wasstirred at room temperature. A solution of di-tert-butyl dicarbonate(BOC-anhydride) (0.086 mol) in DCM (50 ml) was added dropwise and theresulting reaction mixture was stirred at room temperature. An oilprecipitated. Methanol (60 ml) was added and the resulting reactionsolution was stirred for 60 min at room temperature. The solvent wasevaporated. The residue was crystallized from DIPE. The precipitate wasfiltered off and dried, yielding 13.7 g (68.8%) of 1,1-dimethylethyl(trans)-3-hydroxy-4-(hydroxy-methyl)-1-piperidinecarboxylate(intermediate 1-b).

d) Intermediate (1-b) (0.087 mol) was dissolved in chloroform (400 ml)and pyridine (7.51 ml). The solution was cooled to 0° C.4-Methyl-benzenesulfonyl chloride (0.091 mol) was added portionwise over20 minutes. The reaction mixture was stirred and refluxed for 16 hours.More 4-methyl-benzenesulfonyl chloride (1.7 g) and pyridine (1.4 ml)were added and the resulting reaction mixture was stirred and refluxedfor 6 hours, then cooled, washed with citric acid (10% w/w in H₂O),washed with brine, dried, filtered and the solvent was evaporated. Theresidue was purified by flash column chromatography over silica gel(eluent: DCM). The desired fractions were collected and the solvent wasevaporated, yielding 9 g of (intermediate 1-c) as a colourless oil.Intermediate (1-c) (0.13 mol) was separated into its enantiomers bychiral column chromatography over a dynamic axial compression columnwith Chiralcel AD (20 μm. 100 Å, code 061347) (room temperature, columndiameter: 11 cm; eluent: hexane/ethanol 80/20; 50 g product in 5 litersof eluent). Two fraction groups were collected and their solvent wasevaporated, yielding 26.2 g of a first eluting fraction fraction (I) and26 g of a second eluting fraction (II). Fraction (I) was crystallizedfrom DIPE, filtered off and dried, yielding 12.5 g of(+)-1,1-dimethylethyl(trans)-3-hydroxy-4-[[(4-methylphenyl)sulfonyl]oxymethyl]-1-piperidinecarboxylate[intermediate (1-c-I); [α]_(D) ²⁰=+13.99° (c=27.87 mg/5 ml in CH₃OH)].

Fraction (II) was crystallized from DIPE, filtered off and dried,yielding 15 g of (−)-1,1-dimethylethyl(trans)-3-hydroxy-4-[[(4-methylphenyl)sulfonyl]oxymethyl]-1-piperidinecarboxylate[intermediate (1-c-II); [α]_(D) ²⁰=−38.46° (c=25.35 mg/5 ml in CH₃OH].

e) A mixture of intermediate (1-c) (0.023 mol) and benzylamine (0.084mol) in THF (100 ml) was stirred for 16 hours at 125° C. (autoclave).The reaction mixture was cooled. The solvent was evaporated. The residuewas partitioned between DCM and an aqueous K₂CO₃ solution. The organiclayer was separated, dried, filtered and the solvent was evaporated,yielding 15.4 g of 1,1-dimethylethyl(trans)-3-hydroxy-4-[[(phenylmethyl)amino]methyl]-1-piperidinecarboxylate(intermediate 1-d).

f) A mixture of intermediate (1-d) (max. 0.023 mol crude residue) inmethanol (100 ml) was hydrogenated with palladium-on-carbon (10%, 1 g)as a catalyst. After uptake of H₂ (1 equivalent), the catalyst wasfiltered off and the filtrate was evaporated. The residue was solidifiedin DIPE+ACN, filtered off and dried (vacuum, 40° C.), yielding 4 g (76%)of 1,1-dimethylethyl(trans)-4-(aminomethyl)-3-hydroxy-1-piperidine-carboxylate (intermediate1-e, mp. 178° C.).

In an analogous way, but starting fromcis-3-hydroxy-4-piperidinemethanol (described in J. Org. Chem., 34, pp.3674-3676 (1969)), 1,1-dimethylethyl(cis)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate (interm. 1-f)was prepared.

EXAMPLE A.3

a) CaCO₃ (3.9 g) was added to a mixture of 1,3-benzodioxol-4-amine (4.11g) in DCM (40 ml) and CH₃OH (20 ml). This mixture was stirred at roomtemperature. N,N,N-trimethyl benzenemethanaminium dichloroiodate (11.5g) was added portionwise at room temperature. The resulting reactionmixture was stirred for 15 minutes at room temperature. The mixture wasdiluted with water. The layers were separated. The aqueous phase wasextracted with DCM. The combined organic layers were washed with water,dried, filtered and the solvent evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/hexane 80/20). Thepure fractions were collected and the solvent was evaporated. Theresidue was crystallized from DIPE. The precipitate was filtered off anddried, yielding 3.5 g (46.9%) of 7-iodo-1,3-benzodioxol-4-amine(intermediate 2-a).

b) Acetic anhydride (14.25 ml) was added dropwise to a mixture ofintermediate (2-a) (36.6 g) in acetic acid (500 ml), stirred at roomtemperature. The reaction mixture was stirred for 15 minutes at roomtemperature. The reaction mixture was poured out into water (500 ml).The precipitate was filtered, washed with water, then dried, yielding39.29 g (92.6%) of N-(7-iodo-1,3-benzodioxol-4-yl)acetamide(intermediate 2-b).

c) A mixture of intermediate (2-b) (38.8 g), potassium acetae (20 g) andPd/C (10%; 2 g) in CH₃OH (500 ml) was stirred at 150° C. under 4.9×10⁶Pa (50 kg) pressure of CO, during 16 hours. The reaction mixture wascooled, filtered over dicalite, and the filtrate was evaporated. Theresidue was diluted with water, then extracted three times with DCM. Thecombined organic layers were dried, filtered and the solvent evaporated.The residue was dissolved in acetic acid (250 ml) and acetic anhydride(6 ml) was added dropwise. The mixture was stirred for 30 minutes atroom temperature, then diluted with water (250 ml) and the resultingprecipitate was filtered off, washed with water, then dried, yielding19.4 g (64.7%) of methyl 7-(acetylamino)-1,3-benzodioxole-4-carboxylate(intermediate 2-c).

d) A mixture of intermediate (2-c) (18.5 g) and NCS (11.4 g) in ACN (130ml) was stirred and refluxed for one hour. The reaction mixture wascooled. The precipitate was filtered off, washed with ACN, with DIPE,then dried, yielding 18.2 g (87%) of methyl7-(acetylamino)-6-chloro-1,3-benzodioxole-4-carboxylate (intermediate2-d).

e) Intermediate (2-d) (18.2 g) was added to a solution of KOH (37.6 g)in water (380 ml). The resulting reaction mixture was stirred andrefluxed for 3 hours. The mixture was cooled, acidified withhydrochloric acid, and the resulting precipitate was filtered off,washed with water, suspended in ACN, filtered off, then dried, yielding14 g (>95%) of 7-amino-6-chloro-1,3-benzodioxole-4-carboxylic acid(intermediate 2-e). In an analogous way,3,4-dihydro-9-iodo-2H-1,5-benzodioxepin-6-amine (intermediate 2-f) wasprepared.

EXAMPLE A.4

A mixture of intermediate (2-e) (1 g) and 1,1′-carbonylbis-1H-imidazole(0.8 g) in ACN (80 ml) was stirred for 3 hours at room temperature. Thesolvent was evaporated. The residue was partitioned between water andDCM. The organic layer was separated, dried, filtered and the solventwas evaporated. The residue was suspended in DIPE, filtered off, thendried (vacuum), yielding 0.8 g (75%) of1-[(7-amino-6-chloro-1,3-benzodioxol-4-yl)carbonyl]-1H-imidazole(intermediate 3-a).

N-[4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboyl]-1H-imidazole(intermediate 3-b).

In a similar manner were also prepared:

N-[4-amino-5-chloro-2,3-dihydro-7-benzofuranoyl]-1H-imidazole (interm.3-c),

N-[8-chloro-3,4-dihydro-9-acetylamino-2H-1,5-benzdiazepine-6-oyl]-1H-imidazole(interm. 3-d), and

1-[(5-amino-6-chloro-3,4-dihydro-2H-1-benzopyran-8-yl)carbonyl]-1H-imidazoleinterm. 3-e).

EXAMPLE A.5

A mixture of intermediate (1-f) (0.09 mol) and intermediate (3-c) (0.087mol) in ACN (600 ml) was stirred and refluxed for 1 hour. The reactionmixture was cooled to 0° C., and the solvent was evaporated. The residuewas partitioned between DCM and water. The organic layer was separated,dried, filtered and the solvent was evaporated. The residue was purifiedby column chromatography over silica gel (eluent: CH₂Cl₂/(CH₃OH/NH₃)97/3). The pure fractions were collected and the solvent was evaporated.The residue was crystallized from ACN. The precipitate was filtered offand dried), yielding 28.7 g (78%) of (±)-1,1-dimethylethylcis-4-[[[(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl)carbonyl]amino]methyl]-3-hydroxy-1-piperidinecarboxylate(interm. 4. mp. 218° C.).

EXAMPLE A.6

A mixture of intermediate (4) (0.065 mol) in HCl/2-propanol (120 ml) andmethanol (1000 ml) was stirred and refluxed for 30 minutes. The reactionmixture was cooled and the solvent was evaporated. The residue waspartitioned between DCM and NH₃ saturated aqueous NaCl solution. Theorganic layer was separated, dried, filtered and the solvent wasevaporated. The residue was dissolved in 2-propanol and converted intothe hydrochloric acid salt (1:2) with HCl/2-propanol. The precipitatewas filtered off and dried, yielding 14.6 g (64%) of(cis)-4-amino-5-chloro-2,3-dihydro-N-[(3-hydroxy-4-piperidinyl)methyl]-1-benzofurancarboxamidedihydrochloride (interm. 10, mp. 280° C.).

EXAMPLE A.7

a) To a stirred and cooled mixture of ethyl4-oxo-1-piperidinecarboxylate (85.5 g), nitromethane (33.6 g) inmethanol (240 ml), sodium methoxide (10 g) is added dropwise. Uponcompletion, stirring is continued for 2 hours at about 10° C. andfurther overnight at room temperature. The reaction mixture isevaporated at room temperature, crushed ice is added to the oily residueand the whole is acidified with acetic acid. The product is extractedwith trichloromethane, the extract is dried, filtered and evaporated.The oily residue solidifies on triturating in petroleumether. Theproduct is filtered off and dried, yielding 73 g of ethyl4-hydroxy-4-nitromethyl)-1-piperidinecarboxylate (interm. 5).

b) A mixture of intermediate (5) (73 g), methanol (400 ml and aceticacid (150 ml) is hydrogenated in a Parr-apparatus withpalladium-on-carbon (10%, 5 g). After the calculated amount of hydrogenis taken up, the catalyst is filtered off and the filtrate isevaporated. To the residue is added crushed ice and the whole isalkalized with potassium hydroxide. The aqueous phase is salted out withpotassium carbonate and the product is extracted with benzene. Theextract is dried, filtered and evaporated, yielding 63.5 g of ethyl4-(aminomethyl)-4-hydroxy-1-piperidinecarboxylate (interm. 6, mp. 82°C.).

EXAMPLE A.8

a) Intermediate (1-d) was purified and separated into its enantiomers bychiral column chromatography over Chiralcel AD (column n°: AD2000; type:DAC; 20 μM, 1000 Å; column diameter: 11 cm; eluent:hexane/ethanol 80/20injection: 1 g/200 ml). Two pure fraction groups were collected andtheir solvent was evaporated. The first eluting fraction, the(A)-residue, yielded 1,1-dimethylethyl(trans)-3-hydroxy-4-[[(phenylmethyl)amino]-methyl]-1-piperidinecarboxylate(intermediate 25).

b) A mixture of intermediate (25) (0.56 mol) in methanol (700 ml) washydrogenated at 50° C. with palladium-on-carbon (5 g; 10%) as acatalyst. After uptake of hydrogen (1 equivalent), the catalyst wasfiltered off and the filtrate was evaporated. The residue was solidifiedin DIPE, filtered off and dried, yielding 119 g (100%) of(+)-1,1-dimethylethyl(trans)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate (intermediate2-g; [α]_(D) ²⁰=+2.43° (c=24.70 mg/5 ml in CH₃OH)).

c) A mixture of intermediate (3-b) (0.62 mol) and intermediate (2-g)(0.62 mol) in ACN (4300 ml) was stirred and refluxed for 90 minutes. Thesolvent was evaporated. The residue was partitioned between water (1000ml) and ethyl acetate (4000 ml). The layers were separated. The waterlayer was extracted once more with ethyl acetate (1000 ml). The combinedorganic layers were washed with water (2×500 ml), dried, filtered oversilica gel and the solvent was evaporated. 2-Propanol was added, thenevaporated again, yielding 310 g (quantitative yield: used in nextreaction step, without further purification) of 1,1-dimethylethyl(trans)-4-[[[(4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl)carbonyl]amino]methyl]-3-hydroxy-1-piperidinecarboxylate(intermediate 26).

d) A mixture of intermediate (26) (0.011 mol) in a mixture of HCl in2-propanol (12 ml) and methanol (100 ml) was stirred and refluxed for 30minutes. The mixture was cooled and the solvent was evaporated. Theresidue was partitioned between water/NH₃ and DCM. The organic layer wasseparated, dried, filtered and the solvent was evaporated, yielding 2.84g (73%) of(−)-(trans)-4-amino-5-chloro-2,3-dihydro-N-[(3-hydroxy-4-piperidinyl)methyl]-2,2-dimethyl-7-benzofurancarboxamide(interm. 14). A sample (0.5 g) was crystallized from ACN with a drop ofwater, filtered off and dried, yielding 0.2 g of intermediate (14) [mp.116° C.; [α]_(D) ²⁰=−15.91° (c=25.14 mg/5 ml in CH₃OH)].

In this manner and in a similar manner were prepared:

TABLE I-1

Int. No. Ex. No.

OR⁴ Physical data mp. in ° C. 10 A.6

OH cis; .2HCl: mp. 280 11 A.6

OH trans; mp. 198° C. 12 A.6

OH trans 13 A.6

OH trans; .HCl.H₂O 14 A.8

OH (A)-trans; [α]_(D) ²⁰ = −15.91° (c = 25.14 mg/5 ml in CH₃OH) 15 A.6

OH cis 16 A.6

OH cis; .2HCl; mp. 242° C. 17 A.6

OH trans; mp. 190° C. 18 A.6

OH trans; .2HCl; mp. 180° C. 19 A.6

OH trans; .H₂O: mp. 130° C. 20 A.6

OCH₃ cis .C₃H₈O stands for the 2-propanolate salt

TABLE I-2

Int. No. Ex. No.

OR⁴ Physical data mp. in ° C. 21 A.6

OH mp. 205° C. 22 A.6

OH — 23 A.6

OCH₃ — 24 A.6

OCH₃ .1/2C₂H₂O₄ .C₂H₂O₄ stands for the ethanedioate salt

B. Preparation of the Final Compounds

EXAMPLE B.1

A mixture of intermediate (10) (0.019 mol),2-(3-chloropropyl)-2-methyl-1,3-dioxolane (0.029 mol), sodium carbonate(0.076 mol) and potassium iodide (catalytic quantity) in MIK (300 ml,dried over MgSO₂) was stirred and refluxed for 48 hours. The reactionmixture was cooled, filtered and the filtrate was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/(CH₃OH/NH₃) 95/5). The pure fractions were collected and thesolvent was evaporated. The residue was solidified in DIPE (0° C.),filtered off and dried, yielding 5.5 g (64%) of(cis)-4-amino-5-chloro-2,3-dihydro-N-[[3-hydroxy-1-[3-(2-methyl-1,3-dioxolan-2-yl)propyl-]4-piperidinyl]methyl]-7-benzofurancarboxamide(comp. 7, mp. 118° C.).

EXAMPLE B.2

A mixture of intermediate (17) (0.006 mol) and butyraldehyde (0.014 mol)in methanol (150 ml) was hydrogenated with platina-on-carbon (5%, 1 g)as a catalyst in the presence of thiophene (4%, 1 ml). After uptake ofhydrogen gas (1 equivalent), the catalyst was filtered off and thefiltrate was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/(CH₃OH/NH₃) 95/5). Thepure fractions were collected and the solvent was evaporated. Theresidue was solidified in DIPE+ACN. The precipitate was filtered off anddried, yielding 0.53 g of(trans)-8-amino-N-[(1-butyl-3-hydroxy-4-piperidinyl)methyl]-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxamide(comp. 55, mp. 122° C.).

EXAMPLE B.3

A mixture of compound (7) (0.008 mol) in HCl (8 ml) and THF (80 ml) wasstirred and refluxed for one hour. The reaction mixture was cooled, thenalkalized with NH₃/CH₃OH (until pH=14). DCM was added. The organic layerwas separated, dried, filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/(CH₃OH/NH₃) 95/5). The desired fractions were collected and thesolvent was evaporated. The residue was crystallized from ACN. Theprecipitate was filtered off and dried, yielding 1.7 g of(cis)-4-amino-5-chloro-2,3-dihydro-N-[[3-hydroxy-1-(4-oxopentyl)-4-piperidinyl]methyl]-7-benzofurancarboxamide(comp. 4. mp. 118° C.).

EXAMPLE B.4

Compound (38) (10 g) was purified and separated into its enantiomers bychiral column chromatography over Chiralcel AS (20 μm, 1000 Å;eluent:hexane/2-propanol 80/20; injection: 1 g/200 ml). Two purefraction groups were collected and their solvent was evaporated. The(A)-residue was crystallized from DIPE with a small amount of ACN and alittle water. The precipitate was filtered off, washed, and dried,yielding 3.5 g oftrans-(−)-4-amino-5-chloro-2,3-dihydro-N-[[3-hydroxy-1-(3-methoxypropyl)-4-piperidinyl]methyl]-2,2-dimethyl-7-benzofurancarboxamide[compound 39, mp. 96° C., [α]_(D) ²⁰=−12.29° (c=0.5% in CH₃OH)]. Theabsolute configuration was determined to be (3S,4S).

The (B)-residue was crystallized from DIPE with a small amount of ACNand a little water. The precipitate was filtered off, washed, and dried,yielding 3.6 g oftrans-(+)-4-amino-5-chloro-2,3-dihydro-N-[[3-hydroxy-1-(3-methoxypropyl)-4-piperidinyl]methyl]-2,2-dimethyl-7-benzofurancarboxamide[compound40, mp. 97° C.; [α]=+12.72° (c=0.5% in CH₃OH)].

EXAMPLE B.5

A mixture of compound (76) (0.015 mol) in CH₃OH/NH₃ (250 ml) washydrogenated at 10° C. with Raney nickel (3 g) as a catalyst. Afteruptake of hydrogen (2 equivalents), the catalyst was filtered off overdicalite and the filtrate was evaporated, yielding 5.7 g of(±)-trans-5-amino-N-[[1-(2-aminoethyl)-3-hydroxy-4-piperidinyl]methyl]-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide(compound 82).

Table F-1 to F-8 list the compounds that were prepared according to oneof the above Examples.

TABLE F-1

Co. No. Ex. No. -L OR⁴ Physical data 1 B.2 CH₃(CH₂)₃— OH cis; mp. 126°C. 2 B.2 CH₃(CH₂)₃— OH trans; mp. 149° C. 3 B.1 CH₃O(CH₂)₃— OH trans;mp. 136° C. 4 B.3 CH₃CO(CH₂)₃— OH cis; mp. 118° C. 5 B.3 CH₃CO(CH₂)₃— OHtrans; mp. 166° C. 6 B.1

OH trans; mp. 162° C. 7 B.1

OH cis; mp. 118° C. 8 B.1

OH trans 9 B.1

OH trans; mp. 166° C.; .C₂H₂O₄.C₃H₈O 10 B.1

OH trans; mp. 210° C. 11 B.1

OH trans; mp. 180° C. 12 B.1

OH trans; mp. 210° C. 13 B.1

OH trans; mp. 178° C. 14 B.1

OH trans; mp. 220° C. 15 B.1

OH trans; mp. 185.4° C. 16 B.1

OH trans; mp. 120° C.; .H₂O 17 B.1 HO—(CH₂)₂—O—(CH₂)₂— OH trans; mp.118° C. 18 B.1 NC—(CH₂)₃— OH trans; mp. 168° C. 19 B.1 (CH₃)₂CHO(CH₂)₃—OH trans; mp. 119° C. 20 B.1 CH₃—SO₂—NH—(CH₂)₂— OH trans; mp. 168° C. 21B.1

OH trans; mp. 164° C. 22 B.1

OCH₃ trans; mp. 110° C. 23 B.1

OH trans; mp. 144° C. 24 B.1

OH trans; mp. 136° C. 25 B.1

OH trans. mp. 160° C. 26 B.1

OH trans; mp. 166° C. 27 B.1

OCH₃ trans; mp. 130° C. 28 B.3 CH₃—CO—(CH₂)₃— OCH₃ trans; mp. 130° C. 29B.2 CH₃—(CH₂)₃— OCH₃ trans; mp. 130° C. 30 B.1 CH₃—O—(CH₂)₃— OCH₃ trans;mp. 120° C. .C₂H₂O₄ stands for the ethanedioate salt .C₃H₈O stands forthe 2-propanoiate salt

TABLE F-2

Co. Ex. No. No. -L OR⁴ Physical data 31 B.2 CH₃(CH₂)₃— OH trans; mp.120° C. 32 B.1 CH₃O(CH₂)₃— OH trans; .H₂O 33 B.3 CH₃CO(CH₂)₃— OH trans;mp. 138° C. 34 B.1

OH trans; mp. 166° C. 35 B.1

OH trans; .C₂H₂O₄; mp. 166° C. .C₂H₂O₄ stands for the ethanedioate salt

TABLE F-3

Co. Ex. No. No. -L OR⁴ Physical data 36 B.2 CH₃(CH₂)₃— OH trans; mp.138° C. 37 B.1 CH₃O(CH₂)₃— OH trans; .C₂H₂O₄; mp. 197° C. 38 B.1CH₃O(CH₂)₃— OH trans; mp. 100° C. 39 B.4 CH₃O(CH₂)₃— OH (3S-trans,: mp.96° C.; [α]_(D) ²⁰ = −12.29° (c = 0.5% in CH₃OH) 40 B.4 CH₃O(CH₂)₃— OH(3R-trans; mp. 97° C.; [α]_(D) ²⁰ = +12.72° (c = 0.5% in CH₃OH) 56 B.4CH₃O(CH₂)₃— OH (3S-trans; mp. 251.5° C.: .HCl; [α]_(D) ²⁰ = 11.72° (c =0.5% in CH₃OH) 95 B.4 CH₃O(CH₂)₃— OH (3S-trans; .HCl.H₂O 96 B.4CH₃O(CH₂)₃— OH (3S-trans); .HBr.H₂O; mp. 210° C.; [α]_(D) ²⁰ = −10.82°(c = 1% in CH₃OH) 41 B.1 CH₃O(CH₂)₃— OH cis: mp. 150° C. 42 B.1(CH₃)₂CHO(CH₂)₃— OH trans; .(Z)-C₄H₄O₄ 43 B.1 CH₃CH₂O(CO)(CH₂)₂— OHtrans 44 B.1 CH₃CH₂O(CO)(CH₂)₂— OH trans; .(Z)-C₄H₄O₄ 45 B.3HO—CO—(CH₂)₂— OH trans; .HCl .H₂O 46 B.1

OH trans; mp. 190° C. 47 B.1

OH trans 48 B.1

OH trans; .C₂H₂O₄: mp. 120° C. 49 B.3 CH₃—CO—(CH₂)₃— OH trans; mp. 148°C. 50 B.1

OH trans; mp. 202° C. 51 B.2 CH₃(CH₂)₃— OCH₃ trans; .C₂H₂O₄; mp. 132° C.52 B.1 CH₃—O—(CH₂)₃— OCH₃ trans; .C₂H₂O₄; mp. 160° C. 53 B.1

OCH₃ trans; mp. 100° C. .C₂H₂O₄ stands for the ethanedioate salt.(Z)-C₄H₄O₄ stands for (Z)-2-butenedioate salt

TABLE F-4

Co. Ex. No. No. -L OR⁴ Physical data 54 B.2 CH₃(CH₂)₃— OH cis; .HCl.H₂O; mp. 104° C. 55 B.2 CH₃(CH₂)₃— OH trans; mp. 122° C. 57 B.1CH₃O(CH₂)₃— OH trans; mp. 138° C. 58 B.3 CH₃CO(CH₂)₃— OH cis: mp. 138°C. 59 B.3 CH₃CO(CH₂)₃— OH trans; .H₂O 60 B.1

OH trans; mp. 140° C. 61 B.1

OH cis 62 B.1

OH trans 63 B.1

OH trans; .C₂H₂O₄; mp. 180° C. 64 B.1

OH trans; .C₂H₂O₄; mp. 208° C. .C₂H₂O₄ stands for the ethanedioate salt

TABLE F-5

Co. Ex. No. No. -L OR⁴ Physical data 65 B.2 CH₃(CH₂)₃— OH trans; .HCl:mp. 216° C. 66 B.1 CH₃O(CH₂)₃— OH trans .C₂H₂O₄; mp. 176° C. 67 B.3CH₃CO(CH₂)₃— OH trans; mp. 130° C. 68 B.1

OH trans; mp. 154° C. 69 B.1

OH trans; mp. 128° C. 70 B.1

OH trans; .C₂H₂O₄; mp. 188° C. .C₂H₂O₄ stands for the ethanedioate salt

TABLE F-6

Co. No. Ex. No. -L OR⁴ Physical data 71 B.1 CH₃—O—(CH₂)₃— OH trans;.H₂O; mp. 120° C. 72 B.1

OH trans; .H₂O: mp. 120° C. 73 B.1

OH trans; mp. <80° C. 74 B.1 HO—(CH₂)₃— OH trans; .2H₂O; mp. <100° C. 75B.1 HO—(CH₂)₂—O—(CH₂)₂— OH trans; .C₂H₂O₄; mp. 168° C. 76 B.1 NC—CH₂— OHtrans 77 B.1 NC—(CH₂)₃— OH trans; mp. 156° C. 78 B.2 CH₃—(CH₂)₃— OHtrans; .H₂O: mp. 125° C. 79 B.1

OH trans; .H₂O; mp. 115° C. 80 B.3 CH₃—CO—(CH₂)₃— OH trans; mp. 100° C.81 B.1 (CH₃)₂CH—O—(CH₂)₃— OH trans; mp. 100° C. 82 B.5 H₂N—(CH₂)₂— OHtrans 83 B.1

OH trans; mp. 190° C. 84 B.1

OH trans; mp. 175° C. .C₂H₂O₄ stands for the ethanedioate salt

TABLE F-7

Co. Ex. No. No. -L OR⁴ Physical data 85 B.2 CH₃(CH₂)₃— OH mp. 135° C. 86B.1 CH₃O(CH₂)₃— OH mp. 130° C. 87 B.1

OH mp. 134° C. 88 B.3 CH₃—CO—(CH₂)₃— OH mp. 165° C.

TABLE F-8

Co. Ex. No. No. -L OR⁴ Physical data 89 B.2 CH₃(CH₂)₃— OH mp. 174° C.;.C₂H₂O₄ 90 B.1 CH₃O(CH₂)₃— OH mp. 143° C.: .C₂H₂O₄ 91 B.1

OH mp. 174° C.; .C₂H₂O₄ 92 B.1

OH mp. 128° C. 93 B.3 CH₃—CO—(CH₂)₃— OH mp. 130° C. 94 B.1HO—(CH₂)₂—O—(CH₂)₂— OH mp. 115° C.; .(E)-C₄H₄O₄ .C₂H₂O₄ stands for theethanedioate salt .(E)-C₄H₄O₄ stands for the (E)-2-butenedioate salt

C. Pharmacological Examples

C.1. Gastric Emptying of an Acaloric Liquid Test Meal Delayed byAdministration of Lidamidine, in Conscious Dogs

Female beagle dogs, weighing 7-14 kg, were trained to stand quietly inPavlov frames. They were implanted with a gastric cannula under generalanesthesia and aseptic precautions. After a median laparatomy, anincision was made through the gastric wall in the longitudinal directionbetween the greater and the lesser curve, 2 cm above the nerves ofLatarjet. The cannula was secured to the gastric wall by means of adouble purse string suture and brought out via a stab wound at the leftquadrant of the hypochondrium. Dogs were allowed a recovery period of atleast two weeks. Experiments were started after a fasting period of 24hours, during which water was available ad libitum. At the beginning ofthe experiment, the cannula was opened in order to remove any gastricjuice or food remnants.

The stomach was cleansed with 40 to 50 ml lukewarm water. The testcompound was administered I.V. (in a volume ≦3 ml via the venacephalica), S.C. (in a volume ≦3 ml) or P.O. (in a volume of 1 ml/kgbody weight, applied intragastrically via the cannula with a device thatfilled the lumen of the cannula: after injection of the test compound; 5ml NaCl 0.9% was injected in order to correct for the dead space in theinjection system). Immediately after administration of the test compoundor its solvent, lidamidine 0.63 mg/kg was administered subcutaneously.30 min later, the cannula was opened to determine the amount of fluidpresent in the stomach, promptly followed by reintroduction of thefluid. Then the test meal was administered via the cannula. This testmeal consisted of 250 ml distilled water containing glucose (5 g/l) as amarker. The cannula remained closed for 30 min, whereafter the gastriccontents were drained from the stomach to measure total volume (t=30min). For later analysis 1 ml of the gastric contents was taken,promptly followed by reintroduction of the rest volume into the stomach.This sequence was repeated 4 times with 30 min intervals (t=60, 90, 120,150 min).

In the 1 ml samples of the gastric contents, the glucose concentrationswere measured on a Hitachi 717 automatic analyzer by the hexokinasemethod (Schmidt, 1961). These data were used to determine the absoluteamount of glucose that remained in the stomach after each 30 min period,as a measure for the rest volume of the meal itself, independent of acidsecretion.

Curves were fitted to the measurement points (glucose versus time) usingweighed non-linear regression analysis. Gastric emptying was quantifiedas the time needed to empty 70% of the meal (t 70%). The controlemptying time was calculated as the mean t 70% of the last 5 solventexperiments of the same dog. Acceleration of delayed gastric emptying(Δt) was calculated as the time difference between t 70% compound and t70% solvent. To correct for variations in emptying rate between dogs, Δtwas expressed as % of t 70% solvent (Schuurkes et al. 1992)).

TABLE C-1 The acceleration of gastric emptying of a liquid meal delayedby lidamidine in conscious dog was measured for the following compoundsat a dose of 0.01 mg/kg (column ΔT/T^(a)) and 0.0025 mg/kg (columnΔT/T^(b)). Co. No. ΔT/T^(a) ΔT/T^(b) 1 −0.20 −0.23 2 −0.34 −0.61 3 −0.73−0.51 4 −0.08 −0.21 5 −0.36 −0.57 6 −0.52 −0.52 7 0.11 −0.07 9 −0.52−0.24 10 −0.11 −0.15 11 −0.45 −0.19 12 −0.01 −0.03 14 −0.28 — 15 −0.04−0.23 16 −0.08 −0.17 17 0.06 −0.30 18 −0.57 −0.47 19 −0.78 −0.30 20−0.28 −0.20 21 −0.15 −0.21 22 −0.58 −0.37 23 −0.53 −0.15 24 0.01 −0.1325 −0.63 −0.38 26 −0.56 — 27 −0.49 −0.40 28 −0.56 −0.42 29 −0.51 −0.3230 −0.59 −0.55 36 −0.01 — 37 −0.62 −0.41 39 −0.53 −0.43 40 −0.22 −0.1742 −0.12 — 46 −0.43 — 49 −0.28 −0.19 51 −0.45 — 52 −0.18 — 53 −0.47 — 54−0.28 0.04 55 −0.29 −0.18 57 −0.10 −0.03 58 0.09 −0.20 59 −0.13 −0.15 63−0.07 0.12 64 −0.03 −0.32 65 −0.07 — 72 −0.47 0.08 73 −0.52 −0.48 74−0.51 — 75 −0.01 −0.39 76 −0.18 — 77 −0.18 — 78 −0.50 −0.33 79 −0.34 —80 −0.51 −0.11 81 −0.16 — 84 −0.40 — 86 −0.47 −0.33 87 −0.28 — 91 −0.16— 92 −0.45 — 93 −0.03 —

TABLE C-2 The acceleration of gastric emptying of a liquid meal delayedby lidamidine in conscious dog was measured for the followingintermediates at a dose of 0.01 mg/kg (column ΔT/T^(a)) and 0.0025 mg/kg(column ΔT/T^(b)). Intm. No. ΔT/T^(a) ΔT/T^(b) 10 −0.28 −0.04 11 −0.10 0.03 13  0.18 — 17 −0.28 −0.18

What is claimed is:
 1. A compound of formula (I)

a stereochemically isomeric form thereof, an N-oxide form thereof or apharmaceutically acceptable acid or base addition salt thereof, whereinR¹ and R² taken together form a bivalent radical of formula —O—CH₂—O—(a-1), —O—CH₂—CH₂— (a-2), —O—CH₂—CH₂—O— (a-3), —O—CH₂—CH₂—CH₂— (a-4),—O—CH₂—CH₂—CH₂—O— (a-5), —O—CH₂—CH₂—CH₂—CH₂— (a-6), wherein in saidbivalent radicals one or two hydrogen atoms may be substituted withC₁₋₆alkyl, R³ is hydrogen or halo; R⁴ is hydrogen or C₁₋₆alkyl; R⁵ ishydrogen or C₁₋₆alkyl; L is C₃₋₆cycloalkyl, C₅₋₆cycloalkanone, orC₂₋₆alkenyl, Or L is a radical of formula —Alk—R⁶ (b-1), —Alk—X—R⁷(b-2), —Alk—Y—C(═O)—R⁹ (b-3), or —Alk—Y—C(═O)—NR¹¹R¹² (b-4), whereineach Alk is C₁₋₁₂alkanediyl; and R⁶ is hydrogen, hydroxy, cyano,C₁₆alkylsulfonylamino, C₃₋₆cycloalkyl, C₅₆cycloalkanone, or Het¹; R⁷ ishydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₃₋₆cycloalkyl, or Het²; X isO,S, SO₂ or NR⁸; said R⁸ being hydrogen or C₁₋₆alkyl; R⁹ is hydrogen,C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkyloxy or hydroxy; Y is NR¹⁰ or adirect bond; said R¹⁰ being hydrogen or C₁₋₆alkyl; R¹¹ and R¹² eachindependently are hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, or R¹¹ and R¹²combined with the nitrogen atom bearing R¹¹ and R¹² may form apyrrolidinyl or piperidinyl ring both being optionally substituted withC₁₋₆alkyl, amino or mono or di(C₁₋₆alkyl)amino, or said R¹¹ and R¹²combined with the nitrogen bearing R¹¹ and R¹² may form a piperazinyl or4-morpholinyl radical both being optionally substituted with C₁₆alkyl;and Het¹ and Het² each independently are selected from furan; furansubstituted with C₁₋₆alkyl or halo; tetrahydrofuran a tetrahydrofuransubstituted with C₁₋₆alkyl; a dioxolane: a dioxolane substituted withC₁₋₆alkyl a dioxane; a dioxane substituted with C₁₋₆alkyl;tetrahydropyran; a tetrahydropyran substituted with C₁₋₆alkyl;pyrrolidinyl; pyrrolidinyl substituted with one or two substituents eachindependently selected from halo, hydroxy, cyano, or C₁₋₆alkyl;pyridinyl; pyridinyl substituted with one or two substituents eachindependently selected from halo, hydroxy, cyano, C₁₋₆alkyl;pyriniidinyl pyrimidinyl substituted with one or two substituents eachindepentently selected from halo, hydroxy, cyano, C₁₋₆alkyl,C₁₋₆alkyloxy, amino and mono and di(C₁₋₆alkyl)amino; pyridazinyl;pyridazinyl substituted with one or two substituents each independentlyselected from hydroxy, C₁₋₆alkyloxy, C₁₋₆alkyl or halo; pyrazinyl;pyrazinyl substituted with one or two substituents each independentlyselected from halo, hydroxy, cyano, C₁₋₆alkyl, C₁₋₆alkyloxy, amino,mono- and di(C₁₋₆alkyl)amino and C₁₋₆alkyloxycarbonyl Het¹ can alsobearadical of formula

Het¹ and Het² each independently can also be selected from the radicalsof formula

R¹³ and R¹⁴ each independently are hydrogen or C₁₋₄ alkyl; and whereinthe —OR⁴ radical is situated at the 4-position of the central piperidinemoiety.
 2. A compound as claimed in any of claims 1 to 3 wherein L isC₃₋₆cycloalkyl or C₂₋₆alkenyl; or L is a radical of formula (b-1),wherein each Alk is C₁₋₆alkanediyl, and R⁶ is hydrogen, hydroxy, cyano,amino, C₁₋₆alkylsulfonylamino, C₃₋₆cycloalkyl or Het¹, wherein Het¹ istetrahydrofuran; dioxolane; dioxolane substituted with C₁₋₆alkyl;tetrahydropyran; pyridazinyl substituted with one or more substituentsselected from hydroxy, halo and C₁₋₆alkyl; or a radical of formula(c-1), (c-3) or (c-4) wherein R¹³ is C₁₋₄alkyl; or L is a radical offormula (b-2), wherein Alk is C₁₋₆alkanediyl, X is O, and R⁷ isC₁₋₆alkyl or hydroxyC₁₋₆alkyl; or L is a radical of formula (b-2),wherein Alk is C₁₋₆alkanediyl, R⁷ is Het² wherein Het² is pyrazinylsubstituted with C₁₋₆alkyl, and X is NR⁸ wherein R⁸ is hydrogen orC₁₋₆alkyl; or L is a radical of formula (b-3) wherein Y is a directbond, and R⁹ is C₁₋₆alkyl, hydroxy or C₁₋₆alkyloxy; or L is a radical offormula (b-4) wherein Y is a direct bond, and R¹¹ and R¹² are C₁₋₆alkyl,or R¹¹ and R¹² combined with the nitrogen atom bearing R¹¹ and R¹² formpyrrolidinyl.
 3. A compound as claimed in claim 2 wherein L is butyl;propyl substituted with methoxy, methylcarbonyl or2-methyl-1,3-dioxolane; ethyl substituted with 4-methyl-2-pyridazinoneor tetrahydropyranyl; or methyl substituted with tetrahydrofuranyl ortetrahydropyranyl.
 4. A compound as claimed in claim 1 wherein thecompound is(trans)-(−)-4-amino-5-chloro-2,3-dihydro-N-[[3-hydroxy-1-(3-methoxypropyl)-4-piperidinyl]methyl]-2,2-dimethyl-7-benzofurancarboxamide;a pharmaceutically acceptable acid addition salt or an N-oxide formthereof.
 5. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a therapeutically active amount of a compoundaccording to any of claims 1-4.
 6. A process for preparing apharmaceutical composition according to claim 5 wherein atherapeutically active amount of a compound according to any of claims1-4 is intimately mixed with a pharmaceutically acceptable carrier.
 7. Amethod of treating conditions involving a decreased gastro-intestinalmotility comprising administering to a subject in need thereof aneffective amount of a compound according to claim
 1. 8. A compound offormula (III)

a pharmaceutically acceptable acid addition salt thereof or astereochemically isomeric form thereof, wherein R¹, R², R³, R⁴ and R⁵are as defined in claim 1 for compounds of formula (I).
 9. A process forpreparing a compound of formula (I) wherein a) an intermediate offormula (II) is N-alkylated with an intermediate of formula (III) in areaction-inert solvent and, optionally in the presence of a suitablebase,

b) an appropriate ketone or aldehyde intermediate of formula L′═O (IV),said L′═O being a compound of formula L—H, wherein two geminal hydrogenatoms in the C₁₋₁₂alkanediyl moiety are replaced by ═O, is reacted withan intermediate of formula (III);

c) an intermediate of formula (V) is reacted with an carboxylic acidderivative of formula (VI) or a reactive functional derivative thereof;

d) an intermediate of formula (VII), wherein X is bromo or iodo, iscarbonylated in the presence of an intermediate of formula (V) in areaction-inert solvent in the presence of a suitable catalyst and atertiary amine, and at a temperature ranging between room temperatureand the reflux temperature of the reaction mixture;

 wherein in the above reaction schemes the radicals L, R¹, R², R³, R⁴and R⁵ are as defined in claim 1 and W is an appropriate leaving group;e) or, compounds of formula (I) are converted into each other followingart-known transformation reactions; or if desired; a compound of formula(I) is converted into a pharmaceutically acceptable acid addition salt,or conversely, an acid addition salt of a compound of formula (I) isconverted into a free base form with alkali; and, if desired, preparingstereochemically isomeric forms thereof.
 10. A process for preparing acompound of formula (III) wherein a) an intermediate of formula (VIII),wherein PG is an appropriate protective group, is reacted with an acidof formula (VI), or an appropriate reactive functional derivativethereof, in a reaction-inert solvent and subsequent deprotection of theprotecting group PG yielding compounds of formula (III);

 wherein in the above reaction schemes the radicals L, R¹, R², R³, R⁴and R⁵ are as defined in claim 1 and W is an appropriate leaving group;b) or, compounds of formula (III) are converted into each otherfollowing art-known transformation reactions; or if desired; a compoundof formula (III) is converted into an acid addition salt, or conversely,an acid addition salt of a compound of formula (III) is converted into afree base form with alkali; and, if desired, preparing stereochemicallyisomeric forms thereof.